The sequencing of the platypus genome has spurred investigations into the characterisation of the monotreme immune response. As the mostdivergentof extant mammals, the characterisation of the monotreme immune repertoire allows us to trace the evolutionary history of immunity in mammals and provide insights into the immune gene complement of ancestral mammals. The immune system of monotremes has remained largely uncharacterised due to the lack of speciﬁc immunological reagents and limited access to animals for experimentation. Early immunological studies focussed on the anatomy and physiology of the lymphoid system in the platypus. More recent molecular studies have focussed on characterisation of individual immunoglobulin, T-cell receptor and MHC genes in both the platypus and short-beaked echidna. Here, we review the published literature on the monotreme immune gene repertoire and provide new data generated from genome analysis on cytokines, Fc receptors and immunoglobulins. We present an overview of key gene families responsible for innate and adaptive immunity including the cathelicidins, defensins, T-cell receptors and the major histocompatibility complex (MHC) Class I and Class II antigens. We comment on the usefulness of these sequences for future studies into immunity, health and disease in monotremes.